Ca2+-Ionophore-induced secretion of histamine from rat basophil leukemic (RBL-2H3) cell correlated with the hydrolysis of inositol phospholipids but not with the increase in cytosol (Ca(2+)). However, external (Ca(2+)) was obligatory for secretion (J. Biol. Chem. 262:414,1987). The same pattern was observed for release of arachidonic acid. Similarities were noted in release of histamine and arachidonic acid in antigen-stimulated cells. The release of both were enhanced by treatment with cholera toxin and by the presence of andenosine analogs and were inhibited by the phosphodiesterase inhibitor IBMX in either intact or permeabilized cells. Although their release may depend on the generation of the same signals at the level of the membrane the subsequent mechanisms for release probably diverge: the release of arachidonic acid was 4 to 5 times greater with optimal concentrations of A23187 than with optimal concentrations of antigen whereas the reverse was true for release of histamine. Also inhibitors of protein kinase C or depletion of protein kinase (by prolonged exposure of cells to phorbol ester) resulted in reduced secretion of histamine but enhanced release of arachidonic acid upon stimulation of cells with antigen.